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Details on Person UniProt:Q13485 SMAD4
| Class:Id | ReferenceGeneProduct:64628 |
|---|---|
| _chainChangeLog | chain:1-552 added on Fri February 6 2015 |
| _displayName | UniProt:Q13485 SMAD4 |
| _timestamp | 2026-02-20 22:49:17 |
| chain | chain:1-552 |
| checksum | 7EE3C4647712DA90 |
| comment | FUNCTION In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (By similarity). Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling (PubMed:25514493). Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.SUBUNIT Monomer; in the absence of TGF-beta activation (PubMed:9670020). Heterotrimer; on TGF-beta activation (PubMed:15799969). Heterotrimer composed of two molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-SMAD4 complex (PubMed:15350224, PubMed:15799969). Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Found in a complex with SMAD1 and YY1 (By similarity). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes. Interacts with USP9X. Interacts (via the MH1 and MH2 domains) with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Interacts with CITED1 and CITED2. Interacts with PDPK1 (via PH domain) (By similarity). Interacts with VPS39; this interaction affects heterodimer formation with SMAD3, but not with SMAD2, and leads to inhibition of SMAD3-dependent transcription activation. Interactions with VPS39 and SMAD2 may be mutually exclusive. Interacts (via MH2 domain) with ZNF451 (via N-terminal zinc-finger domains) (PubMed:24324267). Interacts with ZC3H3 (By similarity). Interacts weakly with ZNF8 (PubMed:12370310). Interacts with NUP93 and IPO7; translocates SMAD4 to the nucleus through the NPC upon BMP7 stimulation resulting in activation of SMAD4 signaling (PubMed:26878725). Interacts with CREB3L1, the interaction takes place upon TGFB1 induction and SMAD4 acts as a CREB3L1 coactivator to induce the expression of genes involved in the assembly of collagen extracellular matrix (PubMed:25310401). Interacts with DLX1 (PubMed:14671321). Interacts with ZBTB7A; the interaction is direct and stimulated by TGFB1 (PubMed:25514493). Interacts with CREBBP; the recruitment of this transcriptional coactivator is negatively regulated by ZBTB7A (PubMed:25514493). Interacts with EP300; the interaction with this transcriptional coactivator is negatively regulated by ZBTB7A (PubMed:25514493). Interacts with HDAC1 (PubMed:25514493). Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4 transcriptional complex (PubMed:16777850). Interacts (via N-terminus) with TSC22D1 (PubMed:15881652).INTERACTION Cytoplasmic in the absence of ligand. Migrates to the nucleus when complexed with R-SMAD (PubMed:15799969). PDPK1 prevents its nuclear translocation in response to TGF-beta (PubMed:17327236).DOMAIN The MH1 domain is required for DNA binding.DOMAIN The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.PTM Phosphorylated by PDPK1.PTM Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiquitination by USP9X restores its competence to mediate TGF-beta signaling.DISEASE The gene represented in this entry may be involved in disease pathogenesis.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease may be caused by variants affecting the gene represented in this entry.DISEASE SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.DISEASE The disease is caused by variants affecting the gene represented in this entry.SIMILARITY Belongs to the dwarfin/SMAD family.ONLINE INFORMATION Leiden Open Variation Database (LOVD) |
| description | recommendedName: fullName evidence="41"SMAD family member 4 shortName evidence="40"SMAD 4 shortName: hSMAD4 alternativeName: Deletion target in pancreatic carcinoma 4 alternativeName: Mothers against decapentaplegic homolog 4 shortName: MAD homolog 4 shortName: Mothers against DPP homolog 4 |
| geneName | SMAD4 DPC4 MADH4 |
| identifier | Q13485 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Acetylation Cytoplasm Disease variant DNA-binding Isopeptide bond Metal-binding Nucleus Phosphoprotein Proteomics identification Reference proteome Transcription Transcription regulation Ubl conjugation Zinc |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20 |
| name | SMAD4 |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:9000854] ENSEMBL:ENSG00000141646 SMAD4 [Homo sapiens] |
| secondaryIdentifier | SMAD4_HUMAN A8K405 |
| sequenceLength | 552 |
| species | [Species:48887] Homo sapiens |
| (referenceEntity) | [EntityWithAccessionedSequence:170862] SMAD4 [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:177103] SMAD4 [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:193566] SMAD4 [Homo sapiens] [EntityWithAccessionedSequence:2187323] RibC-SMAD4 [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:3310965] SMAD4 D351H [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:3310967] SMAD4 D351G [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:3310970] SMAD4 D351Y [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:3310974] SMAD4 D351del [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:3310983] SMAD4 R361C [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:3310984] SMAD4 R361H [cytosol] [Homo sapiens] |
| (referenceSequence) | [ModifiedResidue:2197649] adenosine diphosphoribosyl (ADP-ribosyl) modified residue at unknown position [ReplacedResidue:3310963] L-aspartic acid 351 replaced with glycine [ReplacedResidue:3310966] L-aspartic acid 351 replaced with L-histidine [FragmentDeletionModification:3310969] Deletion of residues 351 to 351 [ReplacedResidue:3310971] L-aspartic acid 351 replaced with L-tyrosine [ReplacedResidue:3310981] L-proline 356 replaced with L-leucine [ReplacedResidue:3310985] L-proline 356 replaced with L-arginine [ReplacedResidue:3310986] L-arginine 361 replaced with L-histidine [ReplacedResidue:3310989] L-arginine 361 replaced with L-cysteine [ReplacedResidue:3310991] L-arginine 361 replaced with glycine |
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No pathways have been reviewed or authored by UniProt:Q13485 SMAD4 (64628)
